Frontotemporal dementia (FTD) is a common aging-related neurodegenerative disease and shares a wide spectrum of clinical, pathological, and genetic features with amyotrophic lateral sclerosis (ALS). Recent advance in genetics study indicates that pathogenic mutations of most ALS genes are also causative to FTD. Substantial evidence from genetics study suggests Ubqln2 as a causative gene of both ALS and FTD, but how Ubqln2 causes the diseases is not known. Overexpression of Ubqln2 with or without a pathogenic mutation causes indistinguishable phenotypes reminiscent of ALS and FTD, suggesting that pathogenic mutation or excess expression of Ubqln2 is both pathogenic for the diseases. As deletion of the Ubqln2 in knockout rodents does not affect neuronal function, pathogenic Ubqln2 likely causes the diseases through a gain of unknown function. A prominent feature of Ubqln2 related diseases is protein aggregation, which is well reproduced in transgenic rodents overexpressing Ubqln2. Using biochemical approaches, we attempt to unravel how pathogenic Ubqln2 induces neuronal dysfunction via its gained aggregation-prone feature. Our preliminary studies observed that Ubqln2 is deregulated in FTD patients and at miRNA deficiency. The proposed research will determine how deregulated Ubqln2 expression is related to impaired cognitive function and neuronal death in novel rat models and how miRNA deficiency leads to deregulated Ubqln2 expression and to cortical dementia in the diseases. Upon completion, the proposed research will gain a mechanistic insight on Ubqln2 related diseases and likely will identify a network of genes essential to neuronal survival and cognitive function.